Among the mutations identified in my screens for mutants with increased non-disjunction, I have identified one mutation,
me8 ,that defines a cis-acting locus important for promoting normal levels of reciprocal recombination between the two X homologs, thereby ensuring their proper disjunction. The
me8 mutation specifically affects segregation of the X chromosome, and maps near or to the left of
egl-17 ,the leftmost known genetic marker on the X chromosome. Based on previous studies examining the genetic behavior of reciprocal translocations and X chromosome Dps, it had already been proposed that this general region of the X chromosome contains one or more sites involved in normal pairing and segregation of the X homologs (1, 2, 3). The
me8 mutation is semi-dominant:
me8 /me8 hermaphrodites produce 10% self-progeny males, while
me8 /+hermaphrodites produce 1.5% males. This semi-dominance is due to a loss of function, since hermaphrodites heterozygous for chromosomal deletions of the locus (meDf2 -61+)also show an increase in the level of X nondisjunction, producing 8%a males. The fact that
me8 /+is less mutant than Dp+ suggests that the
me8 mutation only partially disrupts the locus, or that there are other similar loci in the deleted region. Increased non-disjunction is not a general property of X chromosome Dfs; Dfs of other regions of X have no effect on X disjunction.
me8 /Dfor Dp; DpDf hermaphrodites show a dramatically high level of X nondisjunction, producing broods composed of >35% males and 6-7% XXX animals. This high non-disjunction in
me8 /Dfand Df/Df is correlated with an 85-90% decrease in recombination between the X homologs, as evidenced both by reductions in genetic map distances and by the presence of univalent (non-crossover) X chromosomes in cytological preparations of oocyte nuclei. Chromosomal duplications of the wild-type region that are unlinked to the X chromosome cannot complement this high rate of non-disjunction in trans, indicating that the locus must act in cis to promote recombination between the X homologs and thereby ensure their disjunction. The data suggest a model in which the
me8 cis-acting locus acts as a "pairing site" involved in nucleating or facilitating the assembly of a recombination-competent complex between the X homologs; this may take place after, or may be required for, a DNA homology search that allows the identification of appropriate pairing partners. The locus might act as a binding site that recruits trans-acting factors onto the chromosomes, initiating assembly of a complex which proceeds in a polar fashion along the length of the homologs. A variation on this model is that the locus serves as a "molecular address", targeting the chromosome to a specific location in the nucleus, presumably the nuclear envelope; this localization then serves to facilitate complex assembly. This type of model is appealing since the
me8 locus maps to the very end of the X chromosome, and chromosome ends are known to be associated with the nuclear envelope during mid-prophase of meiosis (pachytene) in a variety of systems, including C. elegans (4). It was initially a surprise to find that heterozygosity for a deletion of the entire region (meDf6 )implicated in the X;A translocation studies has only a modest effect on X chromosome disjunction, since reciprocal translocations (and Df-translocations isolated in this study) with similar breakpoints cause high non-disjunction and strong crossover suppression. I propose that two factors contribute to the aberrant recombination and segregation behavior observed in translocation heterozygotes: 1) the majority of X has been separated from the cis-acting locus defined by
me8 and the Dfs, and 2) the chromosome has been sequestered to a new location or in a configuration that makes it unavailable to assemble into a recombination-competent complex with its homolog. a Numbers are corrected to account for inviabilily of Df hemizygotes and homozygotes.